Cardiac hypertrophy is associated with adverse cardiovascular events, including an increased risk of arrhythmias and sudden death. Calcineurin, a cytoplasmic protein phosphatase, has been shown to be a major contributor to the pathogenesis of hypertrophic heart disease. Very little is known regarding the role of calcineurin in disease-related electrical remodeling of the heart. The long-term objective of this proposal is to elucidate mechanisms of arrhythmias associated with cardiac hypertrophy and the role of calcineurin therein. The hypothesis is that calcineurin activation triggers electrical remodeling of the adult heart independently and in association with pressure-overload hypertrophy. The specific aims are Aiml: To test the effect of calcineurin activation on the electrophysiological properties of the fully developed adult heart. Transgenic mice that express a regulated, cardiac-specific, constitutively active calcineurin transgene will be studied. In vivo electrophysiology (EP) studies will be performed to measure the electrical characteristics of each murine heart. Susceptibility to inducible ventricular arrhythmias will be tested. Aim2: To define the development of calcineurin-dependent electrical remodeling in relation to the development of cardiac hypertrophy and failure. A time course of the events occurring with calcineurin activation will determine whether electrical remodeling develops independently of hypertrophic growth. Data will be collected using in vivo EP studies, echocardiograms, histological imaging, and molecular analyses. Aim3: To test the role of calcineurin activation in the electrical remodeling that occurs in asssociation with pressure overload hypertrophy. A surgical model of pressure-overload cardiac hypertrophy in mice will be used. Transgenic mice that overexpress modulatory calcineurin-interacting protein 1 (MCIP1), an endogenous inhibitor of calcineurin, will be studied. The results of these experiments will provide much needed insight into the mechanisms of rhythm disturbances associated with cardiac hypertrophy. Investigations such as these are critical to the development of new treatments for arrhythmias and the prevention of sudden cardiac death. Relevance: Over 300,000 Americans per year experience sudden death, in which the heart stops beating with few if any warning signs. Research proposed here will investigate how sudden death occurs in patients with hypertrophic heart disease. The results of this work may lead to more effective strategies for preventing these catastrophic events. [unreadable] [unreadable] [unreadable]